The rapidly growing world population and the high rate of unintended pregnancies make contraception a need and a priority of any public health program. Although several contraceptive methods for women are currently available, it is clear that a more comprehensive approach requires extending contraception to males. However, at present, a safe, effective and reversible contraceptive for men is still unavailable.
The Na,K-ATPase is a protein complex of the cell plasma membrane that uses the free energy from the hydrolysis of ATP to transport Na+ out of the cell in exchange for K+. The transmembrane gradients of Na+ and K+ that the Na,K-ATPase generates are basic for cell survival and are involved in numerous essential cell processes, including cell osmotic balance and volume, cell pH and cell resting membrane potential. The Na,K-ATPase is an heterodimer composed of different molecular forms or isoforms of two main polypeptides, the α and β subunits. The α polypeptide constitutes the catalytic subunit of the Na,K-ATPase, directly involved in coupling ATP hydrolysis to the transport of ions. The β subunit acts as a chaperone protein, controlling the proper folding and trafficking of the α subunit to the plasma membrane. While the presence of an active Na+ and K+ transport system in spermatozoa has been known for some time, it was not until recently, that a novel isoform of Na,K-ATPase, the α4 polypeptide, was discovered in spermatozoa. The α4 isoform is only found in the testis, where it is exclusively expressed in male germ cells after meiosis. The α4 isoform has functional characteristics which are different from the α1 and other Na,K-ATPases, including a remarkably high affinity for ouabain, which is 10,000 fold higher than that of the ubiquitous α1 isoform. Activity of α4 is important for maintaining sperm intracellular Na+ concentration, pH and membrane potential and it is necessary for sperm motility. In addition, recent studies using mouse models have shown that α4 is essential for male fertility.
Currently there is a need for effective and reversible contraceptive agents for men.